The present studies were performed to determine the contribution of EP(2) receptors to renal hemodynamics by examining afferent arteriolar responses to PGE(2), butaprost, sulprostone, and endothelin-1 in EP(2) receptor-deficient male mice (EP(2)-/-). Afferent arteriolar diameters averaged 17.8 +/- 0.8 microm in wild-type (EP(2)+/+) mice and 16.7 +/- 0.7 microm in EP(2)-/- mice at a renal perfusion pressure of 100 mmHg. Vessels from both groups of mice responded to norepinephrine (0.5 microM) with similar 17-19% decreases in diameter. Diameters of norepinephrine-preconstricted afferent arterioles increased by 7 +/- 2 and 20 +/- 6% in EP(2)+/+ mice in response to 1 microM PGE(2) and 1 microM butaprost, respectively. In contrast, afferent arteriolar diameter of EP(2)-/- mice decreased by 13 +/- 3 and 16 +/- 6% in response to PGE(2) and butaprost. The afferent arteriolar vasoconstriction to butaprost in EP(2)-/- mice was eliminated by angiotensin-converting enzyme inhibition. Sulprostone, an EP(1) and EP(3) receptor ligand, decreased afferent arteriolar diameter in both groups; however, the vasoconstriction in the EP(2)-/- mice was greater than in the EP(2)+/+ mice. Endothelin-1-mediated afferent arteriolar diameter responses were enhanced in EP(2)-/- mice. Afferent arteriolar diameter decreased by 29 +/- 7% in EP(2)-/- and 12 +/- 7% in EP(2)+/+ mice after administration of 1 nM endothelin-1. These results demonstrate that the EP(2) receptor mediates a portion of the PGE(2) afferent arteriolar vasodilation and buffers the renal vasoconstrictor responses elicited by EP(1) and EP(3) receptor activation as well as endothelin-1.